-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(3S,10R,16S)-10-[3-Chloro-4-(dimethylamino)benzyl]-16-[2(R),3(R)-epoxy-1(R)-methyl-3-phenylpropyl]-3-isobutyl-6,6-dimethyl-1,4-dioxa-8,11-diazacyclohexadec-13(E)-ene-2,5,9,12-tetraone

【CA登记号】

【分子式】C₃₇H₄₈ClN₃O₇

【分子量】682.26401

【开发单位】Lilly (Originator)

【药理作用】ONCOLYTIC DRUGS

合成路线1 合成路线2 合成路线3

合成路线1

The intermediate 3-chloro-4-amino-D-phenylalanine (V) was synthesized from 4-amino-D-phenylalanine (I). Esterification with a methanolic solution of HCl, prepared from MeOH and AcCl, gave methyl ester (II), and subsequent acylation by means of Ac2O and pyridine afforded diacetamide (III). Halogenation of (III) using N-chlorosuccinimide produced chloride (IV). Basic hydrolysis of (IV) cleaved the methyl ester and one of the acetyl groups, and subsequent treatment with strong acid removed the remaining acetyl group yielding (V).

参考文献中间体

【1】 Schultz, R.M.; Andis, S.L.; Ray, J. E.; Patel, V.F.; Kennedy, J.H.; Novel cryptophycin antitumor agents: Synthesis and cytotoxicity of fragment "B" analogues. J Med Chem 1999, 42, 14, 2588.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	34368	(2R)-2-amino-3-(4-aminophenyl)propionic acid	C₉H₁₂N₂O₂	详情	详情
(II)	34369	methyl (2R)-2-amino-3-(4-aminophenyl)propanoate	C₁₀H₁₄N₂O₂	详情	详情
(III)	34370	methyl (2R)-2-(acetamido)-3-[4-(acetamido)phenyl]propanoate	C₁₄H₁₈N₂O₄	详情	详情
(IV)	34371	methyl (2R)-2-(acetamido)-3-[4-(acetamido)-3-chlorophenyl]propanoate	C₁₄H₁₇ClN₂O₄	详情	详情
(V)	34372	(2R)-2-amino-3-(4-amino-3-chlorophenyl)propionic acid	C₉H₁₁ClN₂O₂	详情	详情

合成路线2

The known methyl ester (VI was hydrolyzed to carboxylic acid (VII) with LiOH in aqueous acetone. After conversion of (VII) to the corresponding succinimidyl ester with N-hydroxysuccinimide and EDC, fluoride-mediated desilylation under acidic conditions furnished alcohol (VIII). Subsequent esterification of (VIII) with the protected amino acid (IX) using EDC and a catalytic amount of DMAP provided intermediate (X). Then, chemoselective coupling of (X) with amino acid (V) was achieved in the presence of N,O-bis(trimethylsilyl)acetamide (BSA) in hot DMF to afford the acyclic precursor (XI). After removal of the Boc group of (XI) with trifluoroacetic acid, the resulting amino acid (XII) was converted to the cyclic depsipeptide (XIII) by macrolactonization under high dilution conditions in the presence of pentafluorophenyl diphenylphosphinate. The aryl amine of (XIII) was protected as the Fmoc derivative (XIV).

参考文献中间体

【1】 Schultz, R.M.; Andis, S.L.; Ray, J. E.; Patel, V.F.; Kennedy, J.H.; Novel cryptophycin antitumor agents: Synthesis and cytotoxicity of fragment "B" analogues. J Med Chem 1999, 42, 14, 2588.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40597	9-[[(chlorocarbonyl)oxy]methyl]-9H-fluorene	28920-43-6	C₁₅H₁₁ClO₂	详情	详情
(V)	34372	(2R)-2-amino-3-(4-amino-3-chlorophenyl)propionic acid		C₉H₁₁ClN₂O₂	详情	详情
(VI)	34373	methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate		C₂₂H₃₄O₃Si	详情	详情
(VII)	34374	(2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid		C₂₁H₃₂O₃Si	详情	详情
(VIII)	34375	1-[[(2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenyl-2,7-octadienoyl]oxy]-2,5-pyrrolidinedione		C₁₉H₂₁NO₅	详情	详情
(IX)	18904	(2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid		C₁₆H₂₉NO₆	详情	详情
(X)	34376	(1S,3E)-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-5-oxo-3-pentenyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate		C₃₅H₄₈N₂O₁₀	详情	详情
(XI)	34377	(10S,13S,15E,19R)-19-(4-amino-3-chlorobenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oic acid		C₄₀H₅₄ClN₃O₉	详情	详情
(XII)	34378	(2R)-3-(4-amino-3-chlorophenyl)-2-[[(2E,5S,6R,7E)-5-([(2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoyl]oxy)-6-methyl-8-phenyl-2,7-octadienoyl]amino]propionic acid		C₃₅H₄₆ClN₃O₇	详情	详情
(XIII)	34379	(3S,10R,16S)-10-(4-amino-3-chlorobenzyl)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone		C₃₅H₄₄ClN₃O₆	详情	详情
(XIV)	34380	9H-fluoren-9-ylmethyl 2-chloro-4-([(3S,10R,16S)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diaza-13-cyclohexadecen-10-yl]methyl)phenylcarbamate		C₅₀H₅₄ClN₃O₈	详情	详情

合成路线3

Further epoxidation of (XIV) with m-CPBA led to a mixture of alpha and beta diastereomeric epoxides, which were separated by RP-HPLC to afford the major beta-epoxide (XV). Deprotection of (XV) with piperidine gave aniline (XVI). This was finally alkylated using iodomethane in the presence of K2CO3 to produce the title dimethylamine.

参考文献中间体

【1】 Schultz, R.M.; Andis, S.L.; Ray, J. E.; Patel, V.F.; Kennedy, J.H.; Novel cryptophycin antitumor agents: Synthesis and cytotoxicity of fragment "B" analogues. J Med Chem 1999, 42, 14, 2588.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	34380	9H-fluoren-9-ylmethyl 2-chloro-4-([(3S,10R,16S)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diaza-13-cyclohexadecen-10-yl]methyl)phenylcarbamate	C₅₀H₅₄ClN₃O₈	详情	详情
(XV)	34381	9H-fluoren-9-ylmethyl 2-chloro-4-[((3S,10R,16S)-3-isobutyl-6,6-dimethyl-2,5,9,12-tetraoxo-16-[(1R)-1-[(2R,3S)-3-phenyloxiranyl]ethyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecen-10-yl)methyl]phenylcarbamate	C₅₀H₅₄ClN₃O₉	详情	详情
(XVI)	34382	(3S,10R,16S)-10-(4-amino-3-chlorobenzyl)-3-isobutyl-6,6-dimethyl-16-[(1R)-1-[(2R,3S)-3-phenyloxiranyl]ethyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone	C₃₅H₄₄ClN₃O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)